Enzymes primarily responsible for protein biosynthesis, such as the amino-acyl-tRNA synthetases, are not apt to be circumvented by other cellular mechanisms; thus, antimetabolites that are capable of species or tissue selective inhibition of these enzymes would be of great value to chemotherapy in general and to cancer chemotherapy in particular. Active-site-directed irreversible inhibitors provide an approach to the achievement of species and tissue selective inhibition of substrate identical enzymes not likely to be obtained with reversible inhibitors. Furthermore, properly designed analogs of an intermediate formed in an enzymic reaction should show intrinsic secificity for the target enzyme with little or no effect on other cellular enzymes; irreversible inhibitors that take advantage of this feature should inherently possess intra-cellular specificity for the target enzyme, and inter-cellular specificity for substrate identical enzymes. A number of ancillary studies shall also be undertaken which should (a) hopefully provide sensitive methods for detection of differences in the synthetases from tumor and normal tissues; (b) provide new methods for the purification of the aminoacyl-tRNA synthetases and amino acid specific tRNA; (c) ascertain the order of substrate binding to the synthetases and certain mechanistic features of these enzymes; (d) demonstrate the utility of functionalized acylated aminoacyl-tRNA. We are also developing methods for affinity chromatography for the steroid receptors and other proteins which regulate transcription and translation and are difficult to purify by conventional methods. BIBLIOGRAPHIC REFERENCES: "A Filter Technique for Measurement of Steroid-Receptor Binding". John D. Baxter, Guy G. Rousseau and Daniel V. Santi, Methods in Enzymol., 37, 234 (1975). "Inhibition of Phenylalanyl-tRNA Synthetase by Aromatic Guanidines and Amidines". Peter V. Danenberg and Daniel V. Santi, J. Med. Chem., 18, 528 (1975).